This integrated preclinical/clinical program application will test CpG oligodeoxynucleotides (CpG ODN) for their ability to enhance host defenses against the human immunodeficiency virus. Our proposals comprise basic research projects based at Case Western Reserve University and Rush Medical College, primate studies at University of California Davis and clinical trials at Case Western Reserve University. The overall goals of these projects are to determine: (1) how CpG ODN (which are known to stimulate innate host defenses) modify host innate and adaptive immune responses in vitro; (2) how CpG ODN can be used as an adjuvant to enhance SIV specific immune responses in a rhesus macaque model; and (3) demonstrate that CpG ODN is an effective vaccine adjuvant in humans. Project 1 "Modulation of APC by CpG ODN: Cytokine Signaling and T Cell Presentation in Human and Murine Systems" will delineate the nature of the stimulatory and inhibitory activities of CpG ODN on antigen presenting cells. Murine and human models will be utilized to dissect the role of IFNalpha/beta induction by CpG to determine how IFNalpha/beta can enhance and down modulate APC function in mice and in HIV-infected humans and in controls. Project 2 "CD1d Restricted T (NKT) Cell Interaction with CpG ODN" will examine the mechanisms whereby CpG ODN expands the population of NKT cells, which are critical to bridging innate and adaptive immunity, in vitro and in vivo. Project 2 also will test the hypothesis that CpG induced activation of plasmacytoid dendritic cells determines the immunomodulatory activity of NKT cells as assessed by IL-4, IFN-gamma, and GM-CSF production. Project 3 "CpG ODN for Therapeutic HIV Vaccines: Non Human Primate Studies" will evaluate how CpG ODN can enhance innate and adaptive antiviral immunity in rhesus macaques immunized with a killed SIV vaccine. The effects of this strategy on antiviral defenses will be evaluated by analytic treatment interruption. Concurrently, the effects of CpG ODN on NKT cell number and function and on IFN-alpha producing cells will be determined. The fourth project: "Immunologic Effects of CpG ODN as Vaccine Adjuvant in HIV Infection" will test the hypothesis that CpG ODN enhances both the magnitude and breadth of pathogen-specific CD8 cell-mediated responses to subunit vaccines. These responses will be compared in HIV infected persons and healthy controls. In addition the effects of CpG ODN on APC function and on NKT cells in vivo will be examined. Overall, this IP/CP application will effectively integrate information gained from basic mechanistic studies into both animal models of HIV infection and human vaccine trials. This application will provide basic and clinical information on the potential use of CpG ODN as a novel immune based therapy for HIV infection and will provide the foundation on which to move forward into larger efficacy studies.